title: Overexpression of the nonpancreatic secretory group II PLA2 messenger RNA and protein in colorectal adenomas from familial adenomatous polyposis patients.
abstract: The synovial fluid or group II secretory phospholipase A2 (sPLA2) has been implicated in various inflammatory processes and has been shown to release arachidonic acid for prostaglandin biosynthesis. In human colorectal cancer, both arachidonic acid and eicosanoid levels are elevated. Recently, sPLA2 has been identified as a candidate gene that modifies the Apc gene in the Min mouse, a murine model for familial adenomatous polyposis (FAP). Loss of sPLA2 gene function results in susceptibility to the Min phenotype and the formation of multiple intestinal polyps, whereas mice expressing an active sPLA2 gene are resistant to polyp formation. Therefore, there are two potentially contrasting roles for sPLA2 in colon cancer; one is protection against polyp formation, and the other, the release of arachidonic acid for prostaglandin production and subsequent tumor promotion. To investigate these contrasting dual roles of sPLA2, we have examined the expression and sequence of the sPLA2 mRNA in normal mucosa and duodenal and colorectal polyps from FAP patients. In 11 of 14 patients, there was a significant increase in sPLA2 mRNA levels in the adenoma over the normal tissue. In some cases, there was over 100-fold increase in mRNA levels in the adenoma compared with normal tissue. Analysis of multiple adenomatous polyps from individual patients revealed that not all polyps contained elevated levels of sPLA2 mRNA. Immunoblot analysis also showed that sPLA2 protein expression was elevated in adenoma over normal tissue in five of six FAP patients analyzed. Furthermore, sequence analysis of sPLA2 mRNA present in these samples did not reveal mutations in the coding region. The implications of the up-regulation of sPLA2 in FAP is not clear, but unlike the Min mouse model, it does not seem to have a significant effect on polyp formation. In contrast, the high level of sPLA2 expression is more likely contributing to the elevated levels of arachidonic acid found in colorectal cancer and, in conjunction with the elevated expression of cyclooxygenase-2, could be another factor in tumor formation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada.
authors.forename: B P
authors.initials: BP
authors.lastname: Kennedy
authors.forename: C
authors.initials: C
authors.lastname: Soravia
authors.forename: J
authors.initials: J
authors.lastname: Moffat
authors.forename: L
authors.initials: L
authors.lastname: Xia
authors.forename: T
authors.initials: T
authors.lastname: Hiruki
authors.forename: S
authors.initials: S
authors.lastname: Collins
authors.forename: S
authors.initials: S
authors.lastname: Gallinger
authors.forename: B
authors.initials: B
authors.lastname: Bapat
mesh_terms: D000236:Adenoma / Q000201:enzymology* / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics; D051546:Cyclooxygenase 2; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004379:Duodenal Neoplasms / Q000201:enzymology; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D054501:Group II Phospholipases A2; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010741:Phospholipases A / Q000096:biosynthesis* / Q000235:genetics; D054467:Phospholipases A2; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2